Pharmaceutically acceptable salts of 4-oxo-4H-chromene-2-carboxylic acid[2-(2- {4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxyphenyl]-amine, as P-glycoprotein inhibitor, are useful as a multidrug resistance inhibitor. PCT Publication No. WO 2005/033097 discloses a preparation method thereof.
According to the publication, as shown in Reaction Schemes 1 and 2, nitro-based compounds (1 and 3) undergo hydrogenation in a solvent such as methanol, ethanol, chloroform, dichloromethane, tetrahydrofuran, ethyl ether and hexane toluene, in the presence of a metal catalyst such as palladium, platinum and zinc to obtain amino compounds (2 and 4). The resulting compound is then subjected to an acylation using a condensing agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N-dicyclohexyldiimide, N,N-diisoprocarbodiimide and 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate, in the presence of a catalyst such as 4-(dimethylamino)pyridine in a solvent such as dichloromethane, chloroform, N,N-dimethylformamide, tetrahydrofuran, and 1,4-dioxane, to obtain a tetrazole compound (5) as a final product.


However, the conventional method may cause safety hazards such as explosion and fire owing to the employment of hydrogen and metal catalyst in large scale production. Also, it further needs a purification process using silica gel column chromatography in order to separate a pure tetrazole compound, which is impractical for large scale production since there are limitations on the size of the column and the amount of loading material in column chromatography. In addition, the chromatography process requires high operational costs due to high-priced column packing material, silica gel, and a large amount of eluent used for the process.